Inflammatory processes occur and contribute to the progression of neurologic dysfunction and neurodegeneration in a broad spectrum of neurologic diseases, including HIV-associated dementia, stroke, spinal cord injury, head trauma, meningitis, autoimmune conditions and brain infections. We have discovered that activated macrophages and microglia synthesize large quantities of the neurotoxin, quinolinic acid, and that this tryptophan metabolite accumulates in brain of patients and experimental animals with inflammatory neurologic diseases. We have continued our search for: 1) inhibitors of quinolinic acid production; 2) appropriate animal models for human quinolinic acid metabolism; 3) appropriate animal models of neurologic disease progression with which to evaluate quinolinic acid synthesis inhibitors. Our results show that human macrophages in culture are a useful screening system to identify kynurenine pathway inhibitors. Gerbils and guinea pigs closely replicate key features of human quinolinic acid metabolism, whereas rats differ in that their macrophages, microglia and astrocytes do not produce quinolinate in response to immune stimuli. Rats also do not show that elevations in brain quinolinic acid levels in response to brain inflammation that characterized human, gerbil and guinea pig responses. We have established that during brain-localized inflammation, quinolinic acid is synthesized locally rather than being derived from blood. Therefore, to attenuate quinolinic acid accumulations during brain inflammation, drugs must enter the brain in order to block local synthesis. 4-Chloro-3-hydroxyanthanilate remains the most potent inhibitor of quinolinic acid synthesis within the brain tested so far. The scope of the investigations will continue to be expanded to include the evaluation of other putative neurotoxic metabolites in inflammatory neurologic diseases. (Formerly LCS)